An animal model of psoriasis in mice deficient in epidermal Jun proteins.
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Animals↗
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Results for “Genes, jun”
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Kainate-induced apoptosis correlates with c-Jun activation in cultured cerebellar granule cells.
We have investigated the involvement of c-Jun in cell death induced by exposure of primary cultures of murine cerebellar granule cells to the glutamate receptor agonist kainate (KA) and evaluated its possible use as a marker for apoptosis. Using cerebellar granule cell neurones from postnatal day 7 mice, we found that 1 hr exposure to KA (1-1000 microM) induced a concentration-dependent neuronal cell death with characteristic apoptotic morphology, including cell shrinkage, neurite blebbing and DNA fragmentation. In addition KA-induced a concentration-dependent expression of c-Jun mRNA and protein as determined by in situ hybridization and immunocytochemistry respectively. DNA fragmentation was detected using terminal transferase-mediated nick-end (TUNEL) labelling and agarose gel electrophoresis. KA-induced cell death was significantly attenuated by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 microM), which shifted the concentration-response curve significantly rightward. The number of apoptotic cell bodies, determined by TUNEL, was also reduced by CNQX (50 microM), with only 15-20% of neurones staining positive after exposure to 1mM KA. In addition, the number of positively stained cells for c-Jun protein and mRNA was substantially reduced by CNQX (50 microM) as determined by random and representative cell counts. These results show for the first time that KA induced apoptotic neuronal death in cultured murine cerebellar granule cells involves the induction of c-Jun mRNA and protein, suggesting the involvement of this immediate early gene in excitotoxic receptor-mediated apoptosis and its potential use as a marker for apoptotic cell death.
Animals↗
Characterization of a SV40-transformed rheumatoid synovial fibroblast cell line which retains genotypic expression patterns: a model for evaluation of anti-arthritic agents.
A chimeric Adenovirus-Simian Virus 40 (AdSV40) containing the large T antigen was used to transform rheumatoid synovial fibroblasts. A rheumatoid synovial fibroblast cell line was established by infection of primary rheumatoid arthritis (RA) synovial fibroblasts at Passage 10 with AdSV40 recombinants followed by selection in semisoft agarose cultures. The transformed cells grew anchor independent, exhibited continuous proliferation (> 65 passages) in monolayer culture, and formed multiple visible foci. The transformed synovial fibroblasts showed expression of the simian virus 40 large T antigen in the nucleus as determined by immunofluorescence staining. In addition, indirect immunofluorescence staining demonstrated that the transformed cells stained specifically with a fibroblast-specific antibody 1B10. Studies involving expression of metalloproteinases showed that collagenase and stromelysin were induced by phorbal 12-myristate 13-acetate (PMA), and such an induction was repressed by dexamethasone typical of primary RA fibroblasts. Levels of mRNAs for IL-1 beta, TNF-alpha, and c-jun were increased by PMA, and the mRNA transcripts of these genes were also repressed by addition of dexamethasone to the culture media. Our results indicate that transformed RA synovial fibroblasts display a similar gene expression pattern in response to PMA and dexamethasone as observed for untransformed primary RA synovial fibroblasts. These transformed rheumatoid arthritis synovial fibroblast cells provide an ideal cell culture model in which to test the efficacy of novel arthritis gene therapy reagents.
Antirheumatic Agents↗
Betaine improves the PCR amplification of GC-rich DNA sequences.
Betaine improves the co-amplification of the two alternatively spliced variants of the prostate-specific membrane antigen mRNA as well as the amplification of the coding cDNA region of c-jun. It is suggested that betaine improves the amplification of these genes by reducing the formation of secondary structure caused by GC-rich regions and, therefore, may be generally applicable to ameliorate the amplification of GC-rich DNA sequences.
Alternative Splicing↗
Affinity selection of DNA-binding protein complexes using mRNA display.
Comprehensive analysis of DNA-protein interactions is important for mapping transcriptional regulatory networks on a genome-wide level. Here we present a new application of mRNA display for in vitro selection of DNA-binding protein heterodimeric complexes. Under improved selection conditions using a TPA-responsive element (TRE) as a bait DNA, known interactors c-fos and c-jun were simultaneously enriched about 100-fold from a model library (a 1:1:20 000 mixture of c-fos, c-jun and gst genes) after one round of selection. Furthermore, almost all kinds of the AP-1 family genes including c-jun, c-fos, junD, junB, atf2 and b-atf were successfully selected from an mRNA display library constructed from a mouse brain poly A(+) RNA after six rounds of selection. These results indicate that the mRNA display selection system can identify a variety of DNA-binding protein complexes in a single experiment. Since almost all transcription factors form heterooligomeric complexes to bind with their target DNA, this method should be most useful to search for DNA-binding transcription factor complexes.
Animals↗
Paclitaxel induces programmed cell death in MDA-MB-468 human breast cancer cells.
The ability of paclitaxel, one of the most active chemotherapeutic agents against breast cancer, to induce programmed cell death in hormone-independent MDA-MB-468 human breast cancer cells was assessed. Treatment of MDA-MB-468 cells led to growth inhibition, high-molecular-weight and oligonucleosomal DNA fragmentation, and apoptosis-associated morphological changes after either 3- or 24-h exposure to paclitaxel concentrations >/=10 nM. Additionally, cleavage products of poly(ADP-ribose) polymerase and lamin B1, two proteins that are cleaved early in the execution phase of programmed cell death, were detected. Quantitative studies indicated that exposure to paclitaxel for 24 h resulted in more DNA fragmentation than did 3-h exposure. Rapid induction of the early-response gene c-jun but not c-myc was associated with paclitaxel treatment. The ability of paclitaxel to induce high-molecular-weight DNA fragmentation and apoptosis-associated morphological changes in three other breast cancer cell lines was also established. These data suggest that paclitaxel, an agent known to stabilize microtubules and prevent cell division but not to act directly on DNA, induces programmed cell death in breast cancer cells.
Antineoplastic Agents, Phytogenic↗
Gene expression analysis of human thymoma correlates with tumor stage.
Thymoma is one of the most common solid tumors in the mediastinum. The recent development of high-density oligonucleotide arrays provides a unique opportunity to generate gene expression profiles of cells from various stages of tumor progression as it occurs in actual neoplastic tissues. We used oligonucleotide arrays to monitor in vivo gene expression levels in early- (stage I or II) and late- (stage IVa) stage thymoma tissues in 36 patients. These in vivo gene expression profiles were verified by real-time quantitative RT-PCR using LightCycler. Using both methods, 2 candidate genes were identified that were more highly expressed in advanced-stage thymomas. One was a well-known gene, c-JUN, and another was an unknown gene, AL050002. AL050002 expression, but not c-JUN expression, was also correlated with the WHO classification (type B3 vs. type B1, B2 or AB). The combined use of oligonucleotide microarray and real-time RT-PCR analyses provides a powerful new approach to elucidate the in vivo molecular events correlated with tumor stage of thymoma.
DNA, Complementary↗
Expression of the immediate early genes c-Fos and c-Jun after head injury in man.
Immediate early genes (IEC) are expressed in a variety of experimental paradigms including cerebral ischemia and trauma. There is a paucity of information on whether the results of laboratory experiments can be extrapolated from animals into man. To examine this further we hypothesized that expression of c-Fos and c-Jun occurs after contusional head injury in man. We also sought to identify whether there was an association between the level of immediate early gene expression and 1. the outcome one year after head injury, 2. the timing of surgery after head injury. IEG expression was examined using in situ hybridization and immunocytochemistry in brain tissue therapeutically removed in 14 patients with head injury 6 h to 6 days after contusional injury. IEG expression was also examined in tissue removed during elective non-traumatic neurosurgery for comparative purposes. Expression of c-fos and c-jun mRNA was observed in 50% and 64% of head-injured patients respectively. Protein immunoreactivity for these IEGs was evident in 67% of head injured patients. The expression of c-Fos and c-Jun was associated with final outcome. Patients with poorer outcomes had higher levels of gene expression (p = 0.08 for c-Fos and p = 0.006 for c-Jun). No correlation between the timing of surgery and the intensity of gene expression was evident in the trauma patients (r2 = 0.09 and 0.10 for c-Fos and c-Jun respectively). In the non-trauma patients 36% expressed c-fos and 73% expressed c-jun mRNA, with all patients studied expressing c-Fos and c-Jun proteins. We conclude that differential expression of c-Fos and c-Jun occurs in the patients with cerebral contusions. The difference in expression rates between mRNA and protein emphasises the need for analysis of gene products when investigating gene expression. These results support the hypothesis that IEGs may be involved in the pathogenetic mechanisms of contusional head injury. Observations of IEG expression in human brain injury are important in steering animal experimental programmes towards studies that may yield information directly applicable to human brain injury.
Adolescent↗
In vivo protein-DNA interactions at the c-jun promoter: preformed complexes mediate the UV response.
Irradiation of cells with UV light triggers a genetic response, called the UV response, which results in induction of a set of genes containing AP-1-binding sites. The c-jun gene itself, which codes for AP-1-binding activity, is strongly (> 100-fold) and rapidly activated by UV. The UV induction of c-jun is mediated by two UV response elements consisting of AP-1-like sequences within its 5' control region. We have analyzed protein-DNA interactions in vivo at the c-jun promoter in noninduced and UV-irradiated HeLa cells. In vivo footprint analysis was performed by using dimethyl sulfate on intact cells and DNase I on lysolecithihin-permeabilized cells in conjunction with ligation-mediated polymerase chain reaction to cover about 450 bp of the c-jun promoter, including the transcription start sites. We find that this region does not contain methylated cytosines and is thus a typical CpG island. In uninduced cells, in vivo protein-DNA interactions were localized to an AP-1-like sequence (nucleotides [nt] -71 to -64), a CCAAT box element (nt -91 to -87), two SP1 sequences (nt -115 to -110 and -123 to -118), a nuclear factor jun site (nt -140 to -132), and a second AP-1-like sequence (nt -190 to -183). These results indicate that complex protein-DNA interactions exist at the c-jun promoter prior to induction by an external stimulus. Surprisingly, after stimulation of c-jun expression by UV irradiation, all in vivo protein-DNA contacts remained essentially unchanged, including the two UV response elements located at the AP-1-like sequences. The UV-induced signalling cascade leads to phosphorylation of c-Jun on serines 63 and 73 (Y. Devary, R.A. Gottlieb, T. Smeal, and M. Karin, Cell 71:1081-1091, 1992). Taken together, these data suggest that modification of the transactivating domain of DNA-bound c-Jun or a closely related factor may trigger the rapid induction of the c-jun gene.
Base Sequence↗
Early events in the neoplastic transformation of respiratory epithelium.
The complex process of epithelial carcinogenesis is composed of discrete biologic events including the early activation events of "initiation" and "promotion." For lung cancer, these events are only now being elucidated. Despite the identification of possible target genes and their mutations, the "initiation" events for lung cancer remain poorly understood. The identification of these "initiation" events is a crucial step toward the development of practical molecular markers for early detection of this disease. The reversible process of tumor promotion remains somewhat enigmatic but is a promising target for chemoprevention. A wide range of substances, including asbestos and various substances in cigarette smoke, behave as tumor promoters for lung cancer. They appear to promote tumor formation by inducing cellular proliferation mediated in part by growth factors. The intracellular signals these factors provide are ultimately translated into cellular growth via steps involving nuclear transcription factors. Early response genes such as the jun and fos gene family members encode such nuclear transcription factors which are expressed in lung cancer cells and primary bronchial epithelial cells. The expression of these transcription factors is highly responsive to stimulation by growth factors including serum, transforming growth factor, and gastrin-releasing peptide. A more thorough understanding of this process will allow the development of molecular and/or pharmacologic antagonists that can interfere with the biologic process of tumor promotion and therefore function as chemoprevention agents.
Biomarkers, Tumor↗
Regulation of jun-B expression by a cyclic AMP (cAMP)-dependent mechanism in human myeloid cells.
The present studies have examined the regulation of the jun-B early response gene by cyclic AMP (cAMP)-dependent signaling pathways. The 2.0-kb jun-B transcript was at low but detectable levels in uninduced human HL-60 myeloid leukemia cells. In contrast, treatment with 1 mmol/L8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) in the presence of isobutylmethylxanthine, an inhibitor of cAMP-dependent phosphodiesterase, was associated with increases in jun-B transcripts that were maximal by 1 hour and then decreased to near pretreatment levels by 6 hours. Similar findings were obtained with 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) and N6,2'-0-dibutyryladenosine 3',5'-cyclic monophosphate (dBt-cAMP). jun-B transcripts were also increased with other agents that increase intracellular cAMP levels, such as prostaglandin E2 (PGE2) and forskolin. Moreover, inhibition of cAMP-dependent protein kinase by the isoquinolinesulfonamide H-8 blocked 8-Br-cAMP-induced increases in jun-B expression. The results of nuclear run-on assays demonstrate that treatment of HL-60 cells with PGE2, forskolin, 8-Br-cAMP, and dBt-cAMP is associated with increases in the rate of jun-B transcription. The present findings also demonstrate that the related jun-D gene is similarly regulated by a cAMP-dependent pathway. Taken together, these findings suggest that stimulation of cAMP-dependent protein kinase is involved in the induction of jun gene expression in myeloid leukemia cells.
Bone Marrow↗
Differentiation-associated genes regulated by TPA-induced c-Jun expression via a PKC/JNK pathway in KYSE450 cells.
A group of potential differentiation-associated genes had been identified by microarray analysis as c-Jun/AP-1 target genes essential for epithelial differentiation program. Our previous study showed that c-Jun/AP-1 could bind and activate these gene promoters in vivo using chromatin immunoprecipitation. To further understand how the mitogen-activated protein kinase signaling pathways regulate AP-1 activity and expression of c-Jun target genes, our strategy was based on the use of 12-o-tetradecanoylophorbol-13-acetate (TPA) and pharmacological reagents to induce or block c-Jun expression. The mRNA and protein expression of these genes increased in response to TPA-induced c-Jun/AP-1 expression. Inhibitors of JNK (SP600125) and PKC (GF109203X) mainly blocked expression and phosphorylation of c-Jun, while inhibition of MEK-ERK activity with PD98059 (an inhibitor of MEK) had little effect. Expression of involucrin and keratin 4 in response to TPA was attenuated by pretreatments with GF109203X and SP600125, but not PD98059, suggesting involvement of PKC and JNK in this response. Taken together, these results suggested that differentiation-associated genes were regulated by TPA-induced c-Jun/AP-1 mainly via a PKC/JNK pathway in esophageal cancer cell line KYSE450.
Cell Differentiation↗
Regulation of c-Jun NH(2)-terminal kinase (Jnk) gene expression during T cell activation.
The c-Jun NH(2)-terminal kinases (JNKs) are a group of mitogen-activated protein (MAP) kinases that participate in signal transduction events mediating specific cellular functions. Activation of JNK is regulated by phosphorylation in response to cellular stress and inflammatory cytokines. Here, we demonstrate that JNK is regulated by a second, novel mechanism. Induction of Jnk gene expression is required in specific tissues before activation of this signaling pathway. The in vivo and in vitro ligation of the T cell receptor (TCR) leads to induction of JNK gene and protein expression. TCR signals are sufficient to induce JNK expression, whereas JNK phosphorylation also requires CD28-mediated costimulatory signals. Therefore, both expression and activation contribute to the regulation of the JNK pathway to ensure proper control during the course of an immune response.
Animals↗
Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein.
Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c- jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c- jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c- jun mRNA with the rank order of potency of PMA approximately endothelin-1>phenylephrine. Up-regulation of c- jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5 M sorbitol) powerfully activates JNKs, but did not increase c- jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c- jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c- jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.
Animals↗
Antimitogenic and mitogenic actions of interleukin-1 in diverse cell types are associated with induction of gro gene expression.
Interleukin-1 (IL-1) is an antiproliferative factor for growing human melanoma A375-C6 cells. To define the molecular basis for the action of IL-1, we set out to identify early genes induced by the cytokine in the absence of de novo protein synthesis. cDNA libraries were constructed from A375-C6 cells that were exposed or unexposed to IL-1 plus cycloheximide. Subtractive hybridization was used to prepare a library that was enriched for IL-1-induced clones. Two of these clones were shown by Northern analysis to represent IL-1-inducible genes. Nucleotide sequencing identified these genes as gro/melanoma growth stimulatory activity, which encodes a cell secretory product, and c-jun, which encodes a transcription factor. IL-1 caused persistent steady state elevation of gro mRNA but only transient induction of c-jun. Northern analysis using gene probes for the transcription factors c-fos and Egr-1 revealed that IL-1 induced c-fos but not Egr-1 expression in these cells. This indicates that differential early gene expression characterizes the growth-inhibitory action of IL-1. In contrast, serum, which is mitogenic for these cells, induces c-jun, c-fos, and Egr-1, but not gro expression. These data imply that in A375-C6 cells, both growth-inhibitory and stimulatory signals can channel their action through c-fos and c-jun genes. As gro induction was specifically associated with the antimitogenic action of IL-1, we studied the effect of the cytokine on gro gene expression in other types of cells. IL-1 was mitogenic for human glioblastoma and monkey kidney epithelial cells and induced gro whereas other mitogens did not. Thus, IL-1 can induce gro gene expression in diverse cell types, whether it acts to stimulate or inhibit proliferation. Like other cytokines gro may play diverse cell-specific roles in growth control.
Animals↗
Activation of Jun kinase is an early event in hepatic regeneration.
Compensatory hepatic regeneration after partial hepatectomy (PH) is dependent upon the extent of resection. This study analyzes the regulation of the AP-1 transcription factor c-Jun during hepatic regeneration. There is a progressive increase in c-jun mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in AP-1 binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun nuclear kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third PH. JNK1 or an immunologically related kinase is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Combining the results of these in vivo and culture studies, we conclude that the minimal stimulation of one-third PH activates JNK, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes.
Animals↗
Angiogenesis and c-Jun.
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Angiogenesis Inhibitors↗
The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting.
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family. In mammalian genomes, three genes encode the JNK family. To evaluate JNK function, mice have been created with deletions in one or more of three Jnk genes. Initial studies on jnk1(-/-) or jnk2(-/-) mice have shown roles for these JNKs in the immune system whereas studies on jnk3(-/-) mice have highlighted roles for JNK3 in the nervous system. Further studies have highlighted the contributions of JNK1 and/or JNK2 to a range of biological and pathological processes. These include bone remodelling and joint disease, inflammatory and autoimmune diseases, obesity, diabetes, cardiovascular disease, liver disease and tumorigenesis in addition to effects in neurons. These results emphasise the differences in the roles played by JNK isoforms in vivo and suggest that the design of JNK inhibitors for subsequent therapeutic uses may benefit from selective inhibition of individual JNK isoforms.
Animals↗